The theme of this grant is to understand how arenaviruses (and viruses in general) trigger the innate immune system in ways that lead to either pathology or immunity. Our overall objective is to understand the complex relationship between viral infection, viral-induced pathology and the generation of immunity. Our underlying hypothesis is that these events are controlled by two classes of molecules with adjuvant-like properties: One class is viral proteins that stimulate the immune system by binding toll-like receptors and the other class is endogenous adjuvant molecules generated by injured cells of the host. The major emphasis is on defining these immunostimulatory molecules/adjuvants and their receptors and then to understand how they might be exploited to modify the course of infection and to develop more effective vaccines. We believe that the results of our proposed experiments will identify new adjuvants that will be useful for generating effective vaccines to arenaviruses and many other pathogens. We will achieve our goals through a collaborative effort between the three component projects, which are highly interactive and complementary. The goal of Project 1 (P.I., Rock) is to elucidate the structure and function of a novel set of adjuvant molecules that are produced by the host when cells are injured, e.g. during a viral infection. The goal of Project 3 (P.I., Finberg) is to identify novel immunostimulatory molecules that are part of the arenavirus itself, determine how they affect immunity and disease and assess their potential to function as adjuvants. The goal of Project 2 (P.I., Golenbock) is to identify the receptors for these immunostimulators/ adjuvants and determine how these receptors function, with a major focus Toll like receptor 2 (because this molecule appears to be unquestionably linked to arenavirus pathogenesis). The interplay between the endogenous adjuvants, viral immunostimulatory molecules, and Toll Like receptors will be examined as a collaborative effort between the three component projects.